Role of p-21-activated kinases in pancreactic cancer

Project Details

Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate of all cancers. Less than 20% of patients are suitable for potentially curative surgery at the time of diagnosis (Vincent et al., 2011). The overall 5-year survival rate for patients with PDAC is less than 5%, and has not improved appreciably in the last 30 years (Vincent et al., 2011; Winter et al., 2012). Gemcitabine-based chemotherapy, remains the main form of treatment for patients with PDAC (Castellanos et al., 2011), with only modest improvements in survival, even when combined with other agents. Cancer progression eventually occurs as cancer cells develop increasing resistance to chemotherapy. The dense stromal component of PDAC and the heterogeneous nature of genetic alterations in PDAC are important factors leading to chemotherapy resistance. There is an urgent need to improve treatment outcomes through the development of more effective chemotherapeutic regimens based on an increased understanding of the molecular mechanisms involved in the development of PDAC.

PDAC develops as a result of a series of genetic mutations, and progresses from non- invasive tumours to invasive and metastatic cancers (Campbell et al., 2010). The most frequent mutations in PDAC, observed in more than 95% of cases, involve the Kras gene (Biankin et al., 2012). The product of the Kras gene is a protein of 21 kDa (p21), which binds to and activates the p21-activated kinases (PAKs). The PAK family of serine/threonine kinases is not only important in carcinogenesis, but also major regulators of cytoskeletal dynamics, with significant roles in cell proliferation and motility (Molli et al., 2009). PAKs can be divided into 2 groups (PAKs 1, 2 and 3, and PAKs 4, 5 and 6) based on sequence homologies. Our published studies in colorectal cancer (CRC) have shown that PAK1 acts at a convergence point where multiple signaling pathways intersect (He & Baldwin, 2013). PAK1 is therefore an attractive therapeutic target, as PAK1 inhibitors should simultaneously block multiple pathways. In fact knockdown of PAK1 abrogates xenograft growth and metastasis of two human CRC cell lines in mice (He et al., 2011). Both PAK1 and PAK2 were identified as candidates in a screen for genes that cooperate with oncogenic Kras to accelerate tumorigenesis and promote progression in mouse PDAC (Pérez-Mancera et al., 2012). In addition two studies have reported that the PAK4 gene is amplified in PDAC (Chen et al., 2008; Kimmelman et al., 2008).

We have recently published that inhibition of PAK activity increases sensitivity PDAC to gemcitabine chemotherapy in vitro and in vivo using PAK inhibitor (Yeo et al., 2014, 2016). We are now going to determine the roles of PAK’s (particularly PAK1 and PAK4) in the development, growth, chemo-sensitivity and survival of PDAC using various models. This includes in vitro and in vivo studies using selective PAK1 and PAK4 inhibitors. Tumour-stroma interactions will be examined by utilization of unique PAK knock-out murine models. The studies proposed in this project will elucidate the effects of targeting individual PAKs on the development and growth of pancreatic cancer, which may lead to significant improvements in treatment outcomes.